The HLA-DQA1*0102/DQB1*0602 genotype is associated with protection from IDDM. This proposal will address the molecular mechanism by which DQ0602 molecule may confer protection. The studies demonstrate that the DQ0602 dimer is a very stable molecule compared to other DQ and DR molecules, as assayed by resistance to SDS denaturation in SDS-PAGE. DQ0602 also has a very high affinity for CLIP; a peptide derived from invariant chain. The hypothesis states that these unique properties of DQ0602 can lead to a disease protective phenotype. The structural basis for the SDS stability of DQ0602 molecules and the biological consequence of this stability will be the focus of this proposal. In this first aim, site-directed mutagenesis will be used to identify the residues within the DQA1*0102 and DQB1*0602 and contribute to stabilization will also be identified. In the second aim, it will be examined that how the antigen processing pathways involving CLIP and HLA-DM are different for DQ0602 from the pathways of the susceptible class II molecules. Subcellular fractionation and confocal microscopy will be used to dissect these pathways. It is postulated that as a result of these structural and functional differences, DQ0602 molecules display distinct peptide repertoires, which influence T cell selection in the thymus and antigen presentation in the periphery. The specificity of autoreactive T cells and the presentation of endogenous and exogenous antigens by DQ0602 and other DQ molecules to T cells will be examined in the last aim. These studies address fundamental immune mechanisms, which account for dominant genetic protection, a major gap in our current understanding of the role of HLA genes in IDDM.